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- PDB-6yr8: Affimer K6 - KRAS protein complex -

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Basic information

Entry
Database: PDB / ID: 6yr8
TitleAffimer K6 - KRAS protein complex
Components
  • Affimer K6
  • GTPase KRas
KeywordsPROTEIN BINDING / Protein complex / Affimer / KRAS / Inhibitor
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / liver development / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / RAF activation / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / visual learning / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding / Signaling by BRAF and RAF1 fusions / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleotide triphosphate hydrolases ...Small GTPase, Ras-type / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsTrinh, C.H. / Haza, K.Z. / Rao, A. / Martin, H.L. / Tiede, C. / Edwards, T.A. / McPherson, M.J. / Tomlinson, D.C.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/P019188/1 United Kingdom
Citation
Journal: Nat Commun / Year: 2021
Title: RAS-inhibiting biologics identify and probe druggable pockets including an SII-alpha 3 allosteric site.
Authors: Haza, K.Z. / Martin, H.L. / Rao, A. / Turner, A.L. / Saunders, S.E. / Petersen, B. / Tiede, C. / Tipping, K. / Tang, A.A. / Ajayi, M. / Taylor, T. / Harvey, M. / Fishwick, K.M. / Adams, T.L. ...Authors: Haza, K.Z. / Martin, H.L. / Rao, A. / Turner, A.L. / Saunders, S.E. / Petersen, B. / Tiede, C. / Tipping, K. / Tang, A.A. / Ajayi, M. / Taylor, T. / Harvey, M. / Fishwick, K.M. / Adams, T.L. / Gaule, T.G. / Trinh, C.H. / Johnson, M. / Breeze, A.L. / Edwards, T.A. / McPherson, M.J. / Tomlinson, D.C.
#1: Journal: Biorxiv / Year: 2020
Title: RAS-inhibiting biologics identify and probe druggable pockets including an SII-alpha3 allosteric site
Authors: Haza, K.Z. / Martin, H.L. / Rao, A. / Turner, A. / Saunders, S.E. / Petersen, B. / Tiede, C. / Tipping, K. / Ajayi, M. / Fishwick, K.M. / Adams, T.L. / Trinh, C.H. / Breeze, A.L. / Edwards, ...Authors: Haza, K.Z. / Martin, H.L. / Rao, A. / Turner, A. / Saunders, S.E. / Petersen, B. / Tiede, C. / Tipping, K. / Ajayi, M. / Fishwick, K.M. / Adams, T.L. / Trinh, C.H. / Breeze, A.L. / Edwards, T.A. / McPherson, M.J. / Tomlinson, D.C.
History
DepositionApr 19, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
Item: _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id ..._pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model
Item: _citation.journal_id_ISSN / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
B: Affimer K6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2554
Polymers31,7872
Non-polymers4682
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1890 Å2
ΔGint-28 kcal/mol
Surface area12800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.574, 71.574, 144.390
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number80
Space group name H-MI41

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Components

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19166.562 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116
#2: Protein Affimer K6


Mass: 12620.499 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.9 Å3/Da / Density % sol: 57.66 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1M sodium acetate, 25% w/v PEG 4000, 0.2M ammonium sulfate, 5% MPD

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 1.9→64.13 Å / Num. obs: 28572 / % possible obs: 100 % / Redundancy: 13.3 % / CC1/2: 1 / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.025 / Net I/σ(I): 13.3
Reflection shellResolution: 1.9→1.95 Å / Redundancy: 11.4 % / Rmerge(I) obs: 2.69 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 2116 / CC1/2: 0.799 / Rpim(I) all: 0.834 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
xia20.5.769data scaling
PHASERphasing
REFMAC5.8.0230refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4OBE, 4N6T

4obe

4n6t


Resolution: 1.9→64.13 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.959 / SU B: 13.377 / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.139 / ESU R Free: 0.135
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2465 1387 4.9 %RANDOM
Rwork0.2109 ---
obs0.2127 27147 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 132.22 Å2 / Biso mean: 64.384 Å2 / Biso min: 38.41 Å2
Baniso -1Baniso -2Baniso -3
1-3.44 Å20 Å20 Å2
2--3.44 Å20 Å2
3----6.88 Å2
Refinement stepCycle: final / Resolution: 1.9→64.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2012 0 29 124 2165
Biso mean--71.4 68.15 -
Num. residues----253
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0142075
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171880
X-RAY DIFFRACTIONr_angle_refined_deg1.291.6822803
X-RAY DIFFRACTIONr_angle_other_deg0.8191.6544392
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3815250
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.4323.028109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.19715375
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3921512
X-RAY DIFFRACTIONr_chiral_restr0.0520.2273
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022290
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02382
LS refinement shellResolution: 1.9→1.949 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.516 100 -
Rwork0.466 2007 -
all-2107 -
obs--99.76 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.5095-0.1352-0.88871.9627-0.39333.1459-0.122-0.1515-0.4151-0.187-0.0372-0.47360.53570.6050.15930.11020.11710.05680.14190.03050.254916.5775-12.001149.9138
21.2805-0.2188-1.16491.3486-1.02615.3590.04010.11680.1558-0.06110.08670.1398-0.227-0.343-0.12680.0532-0.00940.02640.07870.01860.11714.71068.180524.0545
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-1 - 202
2X-RAY DIFFRACTION2B4 - 92

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